rs372481694
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_000077.5(CDKN2A):c.325G>T(p.Ala109Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CDKN2A
NM_000077.5 missense
NM_000077.5 missense
Scores
3
15
Clinical Significance
Conservation
PhyloP100: -0.141
Genes affected
CDKN2A (HGNC:1787): (cyclin dependent kinase inhibitor 2A) This gene generates several transcript variants which differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, the E3 ubiquitin-protein ligase MDM2, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene. [provided by RefSeq, Sep 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM1
In a chain Cyclin-dependent kinase inhibitor 2A (size 155) in uniprot entity CDN2A_HUMAN there are 42 pathogenic changes around while only 12 benign (78%) in NM_000077.5
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.24636382).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDKN2A | NM_000077.5 | c.325G>T | p.Ala109Ser | missense_variant | 2/3 | ENST00000304494.10 | NP_000068.1 | |
CDKN2A | NM_058195.4 | c.368G>T | p.Cys123Phe | missense_variant | 2/3 | ENST00000579755.2 | NP_478102.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.325G>T | p.Ala109Ser | missense_variant | 2/3 | 1 | NM_000077.5 | ENSP00000307101 | P2 | |
CDKN2A | ENST00000579755.2 | c.368G>T | p.Cys123Phe | missense_variant | 2/3 | 1 | NM_058195.4 | ENSP00000462950 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1454012Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 723582
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1454012
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
723582
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 30, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 30, 2024 | The p.A109S variant (also known as c.325G>T), located in coding exon 2 of the CDKN2A gene, results from a G to T substitution at nucleotide position 325. The alanine at codon 109 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. - |
Familial melanoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 25, 2023 | The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 109 of the CDKN2A (p16INK4a) protein (p.Ala109Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma (PMID: 28830923). This variant is also known as c.368G>T (p.Cys123Phe) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 628079). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect CDKN2A (p16INK4a) function (PMID: 12606942). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T;.;.;.;.;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;.;T;.;T;T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;N;.;.;.;.
REVEL
Uncertain
Sift
Benign
T;.;.;T;.;.;.;.
Sift4G
Benign
T;T;T;T;T;T;T;T
Polyphen
P;.;.;.;.;.;.;.
Vest4
MutPred
Loss of catalytic residue at A109 (P = 0.0135);Loss of catalytic residue at A109 (P = 0.0135);.;Loss of catalytic residue at A109 (P = 0.0135);.;.;.;.;
MVP
MPC
0.40
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at